CN102448508A - A method and device for filtering platelets - Google Patents
A method and device for filtering platelets Download PDFInfo
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- CN102448508A CN102448508A CN2010800227443A CN201080022744A CN102448508A CN 102448508 A CN102448508 A CN 102448508A CN 2010800227443 A CN2010800227443 A CN 2010800227443A CN 201080022744 A CN201080022744 A CN 201080022744A CN 102448508 A CN102448508 A CN 102448508A
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- platelets
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- anticoagulant
- platelet
- nanofiber
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- B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
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- B—PERFORMING OPERATIONS; TRANSPORTING
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Abstract
The present invention relates to methods for removing antiplatelet agents and anticoagulants from a platelet preparation. In one embodiment, the method includes the step of flowing the platelet preparation through a filtering tube comprising a filtering membrane and separating the antiplatelet agents and anticoagulants from the platelet preparation by tangential flow filtration, In another embodiment, the method includes the step of passing the platelet preparation through porous material that specifically binds to the antiplatelet agents and anticoagulants.
Description
Invention field
The application requires in the U. S. application serial number 12/792 of submission on June 2nd, 2010; 259 and the U.S. Provisional Application serial number 61/187 submitted on June 15th, 2009; 052 priority; And require in the priority of the U.S. Provisional Application serial number 61/282,306 of submission on January 19th, 2010.This paper is all incorporated in aforementioned all applications by reference into.
The present invention relates generally to hematoblastic preservation, is specifically related to be used for removing from the platelet of storing the method and apparatus of anti-platelet agents and/or anticoagulant.
Background of invention
When blood vessel was damaged, the hematoblastic cell debris that is called as that from bone marrow, discharges adhered to blood vessel wall and forms grumeleuse and loses blood preventing.Normally functioning platelet with sufficient amount for keep blood effectively condense or solidify very important.Sometimes, when health suffers wound or when platelet can not normally play a role, be necessary for the platelet composition of patient's replacing or pumping blood.Generally, with the form of the composition of U/WB or through Plateletpheresis (only from donor, extract platelet and the remainder of blood fail backed to donor again) from volunteer's donor acquisition platelet.Then platelet is flowed to the patient who needs, this process is called as " platelet infusion ".
Under several kinds of condition of different, need the platelet infusion.For example, at intra-operative or because the acute bleeding that causes of wound can cause hematoblastic a large amount of losses in the short time.The platelet infusion is essential for the normal capacity or the hemostasis that recover the control blood flow.In medical domain, individuality can develop and the morbid state that platelet counts reduces, and this is called as thrombocytopenia.Said morbid state possibly be owing to chemotherapy takes place, and needs the platelet infusion to recover normal blood coagulation.
Different with the erythrocyte that can store 45 days, platelet only can be stored 5 to 7 days.Hematoblastic short storage period or storage life have seriously limited the range of application that platelet is supplied with.The consequence of this short retention period is to gather platelet near the hematoblastic time of use, and this makes coordination platelets gathering and platelet supply with the very difficulty that becomes.
A short reason of hematoblastic storage life is that they are activated during gatherer process.Activation process causes platelet microtubule surface externalizing, exposes acceptor site, for example GPIIb/IIIa.Phosphatidylserine residue on the activatory platelet is easy to cause platelet aggregation, gives patient Shi Hui when infusion again and causes cell death (being apoptosis).Therefore, hematoblastic function half life, significantly shorten.
The short Another reason of hematoblastic storage life is that the oxygen supply deficiency has changed hematoblastic metabolic activity.In the environment that lacks sufficient oxygen supply, platelet causes the lactic acid accumulation through anaerobism mechanism.The increase of lactic acid concn causes the reduction of pH, and causes cell death.Though can use the shaking table under the air flow to bathe, platelet is kept in the venting bags, to help overcoming this problem, the expensive and unusual poor efficiency of this store method is not enough to satisfy the hematoblastic oxygen demand of preservation.
Hematoblastic aseptic be difficult to keep, because platelet can not be stored in low temperature, for example-80 ℃ to 40 ℃.As aforementioned, hematoblastic low preservation temperature can start the activation process in the platelet, causes assembling and cell death.But under suitable storage temperature (for example room temperature), the growth of antibacterial can cause hematoblastic germ contamination in the platelet medium, and this is unacceptable for the platelet that is used for infusion.Therefore, food and drug surveilance office (FDA) are defined as 5 days with hematoblastic period of storage, thereby ensure that the infusion supply does not receive germ contamination.
Anti-platelet agents and/or anticoagulant have been used to hematoblastic preservation.When adding these preservation reagent through the platelet of tunica albuginea method (buffy coat method) or the fresh collection of Apheresis (aphaeresis); Can prolong platelet-80 ℃ of storages, keep functional when infusion of hematoblastic stability and they simultaneously to 40 ℃ of temperature ranges.
Yet, before giving patient's infusion, need from storage bag of blood platelet, remove anti-platelet agents and anticoagulant, can bring the misgivings of any side effect thereby eliminate these preservation reagent.
Summary of the invention
One aspect of the present invention relates to the method for from preparations of platelets, removing anti-platelet agents and anticoagulant.Said method comprises that preparations of platelets is flow through contains the filter tube of filter membrane, and passes through tangential flow filtration and from preparations of platelets, separate anti-platelet agents and anticoagulant.
In one embodiment, said filter membrane comprises and is selected from following material: regenerated cellulose, cellulose acetate, polyamide, polysulfones, gather ethyl sulfone (polyethylsulfone) and their combination.
In relevant embodiment, said filter membrane comprises polysulfones or gathers ethyl sulfone.
In another kind of embodiment, the aperture of said filter membrane is molecular cut off 3000 dalton to 0.5 micron.
In another kind of embodiment, the internal diameter of said filter tube is 0.5mm at least.
The method of from preparations of platelets, removing anti-platelet agents and anticoagulant is also disclosed.Said method comprises makes preparations of platelets pass through the porous material that specificity combines anti-platelet agents and anticoagulant.
In one embodiment, said porous material comprises nanofiber.
In relevant embodiment, said nanofiber is cellulose nano-fibrous.
In the relevant embodiment of another kind, said cellulose nano-fibrous diameter is 5-60nm.
In the relevant embodiment of another kind, modify said cellulose nano-fibrously, make it that specific binding site of given anti-platelet agents or anticoagulant can be provided.
In another kind of embodiment, said porous material comprises the enhancing composite membrane that contains 90% polyvinyl alcohol and 10% nanofiber.
In another kind of embodiment, said nanofiber is biodegradable nanofiber.
In relevant embodiment, said biodegradable nanofiber comprise gather (glycolic) (PGA), gather (L-lactic acid) (PLLA), gather (lactic acid-altogether-glycolic) (PLGA) or their combination.
In the relevant embodiment of another kind, chemical modification has been carried out on the surface of said biodegradable nanofiber through oxygen plasma treatment and hydrophilic acrylic acid (AA) situ-formed graft.
In the relevant embodiment of another kind, it is that 200-800nm, aperture are that 2-30 micron and porosity are the porous filter of 94-96% that said biodegradable nanofiber forms thickness.
In another kind of embodiment, said nanofiber is a carbon nano-fiber.
In relevant embodiment, said carbon nano-fiber is the carbon nano-fiber through chemical modification.
The method of utilizing diafiltration from preparations of platelets, to remove anti-platelet agents and anticoagulant is also disclosed.Said method comprises makes preparations of platelets cycle through the hollow-fibre membrane that can from preparations of platelets, separate anti-platelet agents and anticoagulant; Wherein in cyclic process, add diafiltration buffer, to keep the constant volume of preparations of platelets to preparations of platelets.
In one embodiment, said hollow-fibre membrane comprises and is selected from following material: regenerated cellulose, cellulose acetate, polyamide, polyurethane, polypropylene, polysulfones, polyether sulfone, Merlon, nylon, polyimides and their combination.
In another kind of embodiment, said hollow-fibre membrane comprises polysulfones or gathers ethyl sulfone.
In another kind of embodiment, the internal diameter of said hollow filter membrane is 0.5mm at least, and the aperture is molecular cut off 3000 dalton to 0.5 micron.
The method of from preparations of platelets, removing anti-platelet agents and anticoagulant is also disclosed.Said method comprises: make preparations of platelets flow through the filter membrane surface, and from preparations of platelets, separate anti-platelet agents and anticoagulant through tangential flow filtration.
In another kind of embodiment, the aperture of said filter membrane is molecular cut off 3000 dalton to 0.5 micron.
The filter that is used for removing from preparations of platelets anti-platelet agents and anticoagulant is also disclosed.Said filter comprises the process modification and the nanofiber of ability specificity combination anti-platelet agents or anticoagulant.
In one embodiment, said nanofiber is selected from cellulose nano-fibrous, biodegradable nanofiber and carbon nano-fiber.
Brief Description Of Drawings
Fig. 1 is typical case's sketch map of osmosis system continuously.
Fig. 2 illustrates platelet (black line) and the thromboelastogram of (green line) (TEG) afterwards before plasmapheresis that contains inhibitor.
Fig. 3 illustrates platelet (black line) and the TEG of (green line) afterwards before plasmapheresis that contains saline solution.
Fig. 4 illustrates when having inhibitor platelet to the response of TRAP.
Fig. 5 illustrates and removes after the inhibitor platelet to the response of TRAP.
Fig. 6 illustrates when having inhibitor platelet to the response of collagen.
Fig. 7 is illustrated in after the diafiltration platelet to the response of collagen.
Fig. 8 is the sketch map of experimental platelet filtration system.
Fig. 9 illustrates the platelet (black line) that do not contain inhibitor and removes the thromboelastogram of the platelet (green line) after the anti-platelet agents with 15 times of volume-exchange.
Figure 10 illustrates when not having inhibitor platelet to the response of TRAP.
Figure 11 illustrates and carries out 15 times of volume-exchange with Intersol and remove after the inhibitor platelet to the response of TRAP.
Figure 12 illustrates when not having inhibitor platelet to the response of collagen.
Figure 13 illustrates and carries out 15 times of volume-exchange with Intersol and remove after the inhibitor platelet to the response of collagen.
The detailed description of invention
The detailed description that below provides makes art technology, and anyone can implement and utilize the present invention.For the purpose of explaining, list concrete technical term and understand fully of the present invention to provide.Yet, it will be apparent to one skilled in the art that these concrete detailed descriptions are not that embodiment of the present invention is necessary.The description of specifically quoting is only as representative example.The various changes of preferred embodiment will become apparent to those skilled in the art that and without departing from the present invention, the General Principle that this paper limits can be used for other embodiment and application.The present invention is not the embodiment that intention is limited to provide, and should meet the scope as far as possible widely of disclosed principle of this paper and characteristic.
One aspect of the present invention relates to the method for from preparations of platelets, removing anti-platelet agents and anticoagulant.Said method comprises that preparations of platelets is flow through contains the filter tube of filter membrane, and passes through tangential flow filtration separates anti-platelet agents and anticoagulant from preparations of platelets step.
Filtration is pressure-actuated separation process, and this separation process uses film to separate said component based on the size of composition in liquid solution or the suspension with charge differences.Filtration can be divided into two kinds of different operation modes: normal flow filters (NFF) and tangential flow filtration (TFF).In NFF, fluid under applied pressure directly towards the film convection current.The granule that can not pass fenestra too greatly is accumulated in film surface or the filter medium, and less molecule passes through to the downstream.This procedural type also is called as dead-end filtration.
In TFF, fluid is pumped by the tangential along the film surface.Applied pressure is to be used to promote a part of fluid to reach filter liquor one side through film.With the same among the NFF, the granule and the macromole that can not pass fenestra too greatly are trapped within upstream side.Yet in this case, the composition of holding back is not blocked in the film surface.On the contrary, they are washed away by slipstream.This characteristic of TFF makes it become the isolating desirable technology based on reduced size.TFF also is called as cross flow filter usually.Yet the direction of liquid stream with respect to film described in term " tangential ".
In one embodiment, from preparations of platelets, separate anti-platelet agents and anticoagulant, wherein in cyclic process, add diafiltration buffer, to keep the constant volume of preparations of platelets to preparations of platelets through diafiltration.
Diafiltration is from solution " flush away " or remove the TFF method that can see through molecule (impurity, salt, solvent, small protein etc.).But because diafiltration is significantly faster and scale, so usually alternative membrane pipe dialysis of diafiltration.Can diafiltration successfully mainly be determined by the selection to suitable film.Fenestra must be enough greatly allowing permeable material to pass, and must be enough little to hold back bigger material.The experience of initial selected film is to select specified aperture less than any material 2-5 that attempts to hold back times and greater than any material 2-5 film doubly of attempting to pass film.For this purpose, multiple aperture can be used for ultrafiltration and microfiltration category.
The filter membrane that uses among the TFF generally perhaps gathers ethyl sulfone by regenerated cellulose, cellulose acetate or polyamide (as the filter composite material on the polysulfones support), polysulfones and processes.These films have large-scale aperture.The effective aperture defines technology and certain applications.Microfiltration is meant that the aperture of indicating is 0.05 micron to 1.0 microns a film.Micro-filtration membrane can be held back complete cell and cell debris, and colloidal materials, virus, protein and salt are passed through.The molecular weight limit (NMWL) of indicating of ultrafilter membrane is 1-1000kD.They can hold back protein usually, and peptide and salt are passed through.The NMWL of NF membrane and reverse osmosis membrane is less than 1kD.They hold back antibiotic and most of salt, and water and some salt are passed through.
Can carry out chemical modification to these films according to concrete application, make it that more positive charge or negative charge can be provided, thus binding purpose solute optionally.Selectively, can modify the surface chemistry of these films, make it combine purpose solute by specificity such as anti-platelet agents or direct thrombin inhibitor.
In certain embodiments, said film is a hollow-fibre membrane.The TFF that utilizes hollow-fibre membrane accomplishes through the internal diameter that from handle storage, Treatment Solution is pumped into tubular fiber.Hole in the wall of said fiber allows permeable material to pass, and big material is retained in the main fluid.Then, main fluid continues to pass to " seepage remaining liquid " end of fiber, and turns back to the processing storage that it is pumped out.Through with see through the speed (continuous diffusion) that liquid stream equates or be concentrated into the mode of redilution (discontinuous diafiltration) after the certain level that storage adds alternative buffer or diafiltration takes place cleaning solution to handling.Two kinds of methods all cause seeing through the concentration reduction of material, and the material of holding back simultaneously is retained in the solution that cycles through the slipstream system gently.
Fig. 1 shows typical continuous diffusion system, wherein through vacuum draw buffer is added to automatically and handles in the storage.Said system comprises pump (a), pressure measuring device (b), flow measurement (c), handles storage (d), buffer storage (e) and hollow fiber filter assembly (f).Pump make Treatment Solution with controlled flow velocity and shear rate from handling storage through filter and return container handling and circulate.In this recirculation circuit, carry out pressure measxurement to control and to write down driving force through film.The careful permeate flow velocity of measuring can be realized handling expansion accurately and handling and optimize.Just realize diafiltration through adding diafiltration buffer simply to this closed circuit.When utilizing hollow-fiber module work, pipe and airtight salable bottle are the simple utensils that carries out continuous diffusion.
In order in airtight system, to begin diafiltration, need in container handling, form vacuum.Can be immersed in this point of realization in the diafiltration buffer bottle through buffer being added pipe, as shown in Figure 1.Along with the permeate outflow system, the vacuum in the encapsulation process storage is drawn to buffer wherein with the flow velocity identical with processing flux.When in the permeate container, collecting the diafiltration buffer of target volume, can come termination through stopping permeate vacuum seal mobile and that destroy on the charging storage simply.
When leak-tight system can't realize,,, can control the buffer interpolation it is conformed to the permeate flow velocity through using single head or double end two stage pump to add buffer to the charging storage or handling in the storage particularly for test and production-scale processing.Sometimes, reduce through concentrating that to handle volume be favourable before the diafiltration.Need remove the buffer volume that can see through material and handle and have certain relation in the storage between the product liquor capacity.Through understanding this relation, can minimization time and the long-pending relevant cost of buffering liquid.
The anti-platelet agents that uses hereinafter is meant and stops platelet activation and/or accumulative any reagent reversiblely.Can stop platelet activation and/or accumulative reagent to include but not limited to: heparin, heparin substitute, short thrombosis anticoagulant, platelet phosphodiesterase inhibitor, dextran etc. or their mixture.The instance of heparin and heparin substitute includes but not limited to calciparine, like calcium antidimmer (calciparin); Low molecular weight heparin is like Enoxaparin (enoxaparin and lovenox); Heparin sodium is like heparin, lipo-hepin, liquaemin (liquaemin sodium) and panheprin; And dihydroergotamine mesilate heparin sodium.Suitable short thrombosis anticoagulant is anisindione (anisindione), dicoumarol (dicumarol), warfarin sodium (warfarin sodium) or the like for example.Being fit in the present invention, the instantiation of the phosphodiesterase inhibitor of use includes but not limited to anagrelide (anagrelide), dipyridamole (dipyridamole), pentoxifylline (pentoxifyllin) and theophylline (theophylline).The embodiment of dextran such as macrodex; Like HYSKON
(Cooper Surgical; Inc.; Shelton, Connecticut, U.S.A.) and MACRODEX
(Pharmalink; Inc.; Upplands Vasby, Sweden), and Dextran 75; Like GENTRAN
75 (Baxter Healthcare Corporation; Deerfield, Illinois, U.S.A.).
Anti-platelet agents includes but not limited to combine with reversible manner the active agent and the non-steroidal anti-inflammatory drug (NSAID) in GPIIb/IIIa site.In preferred compositions, be used for combining or the active agent that links had 4 hours or circulation still less suppresses half life with the GPIIb/IIIa site.Being used for combining the instance of the suitable anti-platelet agents in GPIIb/IIIa site with reversible manner is eptifibatide (eptifibatide) (INTEGRILIN
Schering-Plough Corporation; Kenilworth; New Jersey; U.S.A.), orbofiban (orbofiban), xemilofiban (xemilofiban), lamifiban (Lamifiban), tirofiban (tirofiban), abciximab (abciximab), XJ757, DUP728, XR299, linearity or new ring-type RGD peptide analogues, cyclic peptide, peptide mimics and with conjugated non-peptide analogues of nitric oxide donor or the like, and above mixture.
Non-steroidal anti-inflammatory drug (NSAIDS) obtains and is generally used for treating inflammation easily.Usually, NSAIDS has Salicylate spline structure or non-Salicylate structure.Be suitable for NSAIDS of the present invention and can be at the reversible combination of external ability and anticoagulant but when injecting, removed Salicylate appearance or the non-Salicylate NSAIDS of (removing fast) (general, in) rapidly less than about 2 hours from health.Being suitable for NSAIDS of the present invention includes but not limited to; Salicylate appearance NSAIDS for example; Like acetaminophen, carprofen (carprofen), choline salicylate, magnesium salicylate, salicylamide, sodium salicylate, sodium thiosulfate or the like, and their mixture.The instance of non-Salicylate NSAIDS includes but not limited to; Diclofenac sodium, diflunisal (dfifunisal), etodolac (etodolac), fenoprofen calcium (fenoprofen calcium), flurbiprofen (flurbiprofen), oxychloroquine (hydroxychloroquin), ibuprofen (ibuprofen), indomethacin (indomethacin), ketoprofen (ketoprofen), ketorolac trometamol (ketorolac tromethamine), meclofenamate sodium (meclofenamate sodium), mefenamic acid (mefenamic acid), nabumetone (nabumetone), naproxen (naproxen), naproxen sodium, crovaril (oxyphenbutazone), Phenylbutazone (phenylbutazone), piroxicam (piroxicam), sulfinpyrazone (sulfinpyrazone), sulindac (sulindac), tolmetin sodium (tolmetin sodium), dimethyl sulfoxine or the like, and their mixture.
Thereby anti-platelet agents also comprises any reagent that the chemical pathway that suppresses in the platelet causes platelet activation to reduce.Usually, suppressing chemical pathway and causing the reagent of platelet activation minimizing is calcium chelating agent, like calcium channel blocker, α-Zu Zhiji, receptor, blocker or the like, and their mixture.The instance more specifically of calcium chelating agent includes but not limited to; The acid citrate dextrose anti-freezing liquid of acid citrate dextrose anti-freezing liquid, improvement, anticoagulant citrate phosphate dextrose adenine solution, anticoagulant sodium citrate solution, anticoagulant citrate phosphate dextrose solution, potassium oxalate, sodium citrate, Disodium oxalate., amlodipine (amlodipine), BP Bepridil hydrochloride (bepridil hydrochloride), diltiazem hydrochloride (diltiazem hydrochloride), felodipine (felodipine), isradipine (isradipine), Licardipine Hydrochloride (nicardipine hydrochloride), nifedipine (nifedipine), nimodipine (nimodipine), verapamil hydrochloride (verapamil hydrochloride), Carclura (doxazosin mesylate), phenoxybenzamine hydrochloride (phenoxybenzamine hydrochloride), phentolamine mesylate (phentolamine mesylate), minipress (prazosin hydrochloride), terazosin hydrochloride (terazosin hydrochloride), tolazoline hydrochloride (tolazoline hydrochloride), Acebutolol (acebutolol hydrochloride), atenolol (atenolol), betaxolol hydrochloride (betaxolol hydrochloride), bisoprolol fumarate (bisoprolol fumarate), carteolol hydrochloride (carteolol hydrochloride), esmolol hydrochloride (esmolol hydrochloride), Baratol (indoramine hydrochloride), labetalol hydrochloride (labetalol hydrochloride), Levobunolol Hydrochorid (levobunolol hydrochloride), hydrochloric acid metipranolol (metipranolol hydrochloride), spectinomycin hydrochloride (metoprolol tartrate), nadolol (nadolol), penbutolol sulfate (penbutolol sulfate), pindolol (pindolol), propranolol hydrochloride (propranolol hydrochloride), terazosin hydrochloride (terazosin hydrochloride), timolol maleate (timolol maleate), guanadrel sulfate (guanadrel sulfate), guanethidine monosulphate (guanethidine monosulfate), metirosine, reserpine (reserpine) or the like, and their mixture.
Anticoagulant comprises: the Xa inhibitor, like DX-9065a, RPR-120844, BX-807834 and SEL series of X a inhibitor; The IIa inhibitor, like DUP714, HIRULOG (hirulog), Argobatran and hirudin (hirudin), and their mixture; And other peptides simulation Xa inhibitor or non-peptide Xa inhibitor, IIa inhibitor, or their mixture.Below will discuss wherein some inhibitor in more detail.
In preferred embodiments, the removal of anti-platelet agents and anticoagulant will be referred to utilize the tangential flow filtration of micro-filtration membrane.The micro-filtration membrane material includes but not limited to: regenerated cellulose, cellulose acetate, polyamide, polyurethane, polypropylene, polysulfones, gather ethyl sulfone, Merlon, nylon, polyimides and their combination.In one embodiment, micro-filtration membrane is by polysulfones or gathers the hollow-fibre membrane that ethyl sulfone is processed.In another embodiment, the internal diameter of filter membrane pipe is 0.5mm or bigger, and membrane aperture is 0.05 micron or bigger.In another embodiment, the aperture of film is molecular cut off 3000 dalton to 0.5 micron.
In another embodiment, preparations of platelets with 150ml/ minute to 370ml/ minute flow velocity through the doughnut film filter.These flow velocitys provide the acceptable shearing force of 2000-s to 4000-s.Acceptable pump provides large-scale flow velocity, and the continuous monitoring of inlet, seepage remaining liquid, permeate and transmembrane pressure also is provided.In one embodiment, pump be Kros Flow II pump (Spectrum Labs, Rancho Dominguez, California).The fluid infusion that is suitable for removing anti-platelet agents and anticoagulant is the liquid that is used for platelet storage.Usually, 10-15 times of volume-exchange can cause removing the interpolation reagent greater than 99%.Usually, can remove the anti-platelet agents (like eptifibatide (Etifibatide)) of 45-100 μ g and the anticoagulant (like Argobatran) of 2.5-10mg.Usually, the 1 unit platelet that is obtained by the tunica albuginea method contains 3 * 10 in about 300 milliliters of blood plasma or other suitable preservation solution
11Individual platelet.Platelet by the Apheresis collection contains 5 * 10 usually in 250 milliliters of blood plasma or other suitable preservation liquid
9Individual platelet.
In another embodiment, preparations of platelets was with 20-400ml/ minute, and preferred 150-400ml/ minute flow velocity is through the hollow fiber filter in the percolating device.The aperture is that molecular cut off 3000 dalton's to 0.5 micron doughnut film filter is acceptable.Preferred aperture is 0.05 micron.Be the platelet (300-400ml) that exchanges 1 unit, the preferred surface area of filter assemblies is 2500cm
2If associating 370ml/ minute flow velocity can allow in 15 minutes, to remove fully anti-platelet agents and the anticoagulant that comprises in (>99%) 1 unit platelet.Diafiltration buffer can be any solution that is suitable for platelet storage.In one embodiment, diafiltration buffer is the platelet storage solution (T-Sol) that contains 20% blood plasma of commercially available acquisition.
Another aspect of the present invention relates to the method for from preparations of platelets, removing anti-platelet agents and anticoagulant.Said method comprises makes preparations of platelets pass through the step that specificity combines the porous material of anti-platelet agents and anticoagulant.
In certain embodiments, porous material comprises nanofiber.The instance of nanofiber includes but not limited to cellulose nano-fibrous, biodegradable nanofiber and carbon nano-fiber.
Can be obtained cellulose nano-fibrously through chemical treatment and follow-up advanced machinery technology by various sources, said source is flax bast fiber, hemp, kraft pulp and turnip for example.The diameter of the nanofiber that so obtains is 5-60nm.Through AFM and the cellulose nano-fibrous ultrastructure of transmission electron microscope research.Also aspect degree of crystallinity, characterize cellulose nano-fibrous.In one embodiment, film filter is the enhancing composite membrane that comprises 90% polyvinyl alcohol and 10% nanofiber.
Can modify the chemical property of these cellulose fibres, make it can provide given anti-platelet agents and anticoagulant to have specific binding site.Can be with these fiber package quilts in the current obtainable disposable filtering platform surface of (for example being used for the gobbet sterilization).
Can with such as gather (glycolic) (PGA), gather (L-lactic acid) (PLLA) with gather (lactic acid-altogether-glycolic) Biodegradable polymeric (PLGA) and be dissolved in individually in the suitable solvent, then they are carried out electricity and spin process to process the nanofiber skeleton.Then, can use oxygen plasma treatment and situ-formed graft hydrophilic acrylic acid (AA) that chemical modification is carried out on their surface.In one embodiment, the fiber thickness of biodegradable nanofiber skeleton is 200-800nm, and the aperture is that 2-30 micron and porosity are 94-96%.
The ultimate tensile strength of PGA is average about 2.5MPa, and the ultimate tensile strength of PLGA and PLLA is less than 2MPa.The elongation at break of three kinds of nanofiber skeletons is 100-130%.When the test grafting during surface characteristic of skeleton of AA, identify higher carbon ratio, lower contact angle and carboxylic group (existence COOH).Utilize Cement Composite Treated by Plasma and AA grafting, the hydrophilic functional group can successfully be added in the surface of electro spinning nano fiber skeleton.The skeleton of these finishinges provides and has added the necessary site of part that specificity combines given anti-platelet agents and anticoagulant.
Can utilize several method to convert activated carbon to bioactive fiber.The carbon nano-fiber that provides instance to prove these modifications can be provided for combining carboxyl, hydroxyl and other chemical reaction sites of any purpose part.
Can be by chemical vapour deposition technique (CVD) synthesize nano carbon fiber (CNF).Can be with being adsorbed on the CNF such as the aminoacid of alanine, aspartic acid, glutamic acid with such as the enzyme of glucoseoxidase (GOx).Through the concentration in pH value, acid/alkali site and the characteristic (hydrophilic or hydrophobicity) of naphthalene absorption representation CNF.These fibers are easy and the purpose part is crosslinked, promptly can selective binding anti-platelet agents and anticoagulant.
The present invention relates to the filter tube that is used for removing from preparations of platelets anti-platelet agents and anticoagulant on the other hand.The internal diameter of said filter tube is 0.5mm at least, and has the filter membrane that the aperture is molecular cut off 3000 dalton to 0.5 micron.
The present invention relates to the filter that is used for removing from preparations of platelets anti-platelet agents and anticoagulant on the other hand.Said filter comprises the process modification and the nanofiber of ability specificity combination anti-platelet agents or anticoagulant.
In relevant embodiment, nanofiber is a kind of in cellulose nano-fibrous, biodegradable nanofiber and the carbon nano-fiber.
Following examples have been set forth the present invention further, and said embodiment should not be interpreted as restriction the present invention.The content of all lists of references of being quoted among the application, patent and disclosed patent application and figure and table is incorporated herein by reference.
Embodiment 1: utilize diafiltration to remove INTEGRILIN
Based on following measurement, having set up concentration is the standard UV absorption curve of the Integrilin of 3-50 μ g/ml at the 214nm place:
Make the test fluid that contains 50 μ g/ml Integrilin cycle through hollow fiber filter (Spectrum Laboratories X20S-300-O2S) with 100ml/ minute circulation rate.In brief, be that 0.710 test fluid places gas-tight container with initial OD 214.Along with test fluid cycles through hollow fiber filter, the seepage remaining liquid volume reduces.Use the liquid volume that substitutes loss from the fresh liquid of second container.After the long-pending exchange of circulation in about 10 minutes and hexaploid, the OD214 of test fluid is less than 0.01.
Embodiment 2: from platelet concentrate, remove inhibitor
In an experiment, use the platelet concentrate that obtains by the tunica albuginea method in the research.48 microgram GPIIb/IIIa inhibitor Integrilin (eptifibatide) and the synthetic thrombin inhibitor Argabotran of 2.4mg are added in the 350ml platelet.Begin to remove inhibitor through diafiltration.Be utilized in the solution that the 60ml that is purchased preparation in the platelet storage solution (T-Sol) contains 20% FFP the 15ml platelet concentrate is carried out diafiltration.Sample preservation is spent the night, and second day through thromboelastogram (TEG) and utilize standard antagonist (for example TRAP and collagen) to measure platelet function property.Fig. 2 illustrates specimen (black line) and TEG scanning of (green line) afterwards before diafiltration.Fig. 3 illustrates control sample (platelet that contains saline solution) (black line) and TEG scanning of (green line) afterwards before diafiltration.Result among Fig. 3 shows and removes most of inhibitor through diafiltration.Fig. 4 illustrates inhibitor and has following response to TRAP.Fig. 5 illustrates the response of removing after the inhibitor TRAP.Fig. 6 illustrates inhibitor and has down the response to collagen, and last Fig. 7 illustrates after the diafiltration response to collagen.
In another experiment, Integrilin and Argabotran added doubly being added to (i.e. interpolation 48 microgram Integrilin and 2.4mgArgatroban in the 350ml platelet) in the platelet unit with 3 of treatment concentration.Before adding inhibitor, obtain the base-line data of platelet function property.These base-line datas comprise the thromboelastogram of assessment overall platelet function and set strength and test as the TRAP test and the collagen of other sign of platelet function property.
Utilize the airtight conical flask of 50ml, surface area to be 240cm
2Polysulfone hollow fibre cross-flow assembly, in the 40ml sample, carry out diafiltration (Fig. 8).Add the continuous exchange that solution (Intersol) carries out with the standard platelet of cumulative volume and show that the inhibitor that is exchanged for of 15 times of volumes provides optimum.The aperture of selected hollow-fibre membrane is 0.05 micron.The aperture can be molecular cut off 3000 dalton to 0.5 micron.Can use and anyly at present obtainablely be used to store hematoblastic interpolation solution and carry out the exchange of 15 times of volumes.
After 15 times of volume-exchange, FFP of the same race is added in the platelet, to reach the PC of 25% (v/v).This operation is essential, because blood plasma can provide the soluble component that solidifies, thereby allows to carry out functional test.
(containing among the 30% blood plasma Intersol), hematoblastic recirculation rate was set to 370ml/ minute.Through calculating the shearing force that can form about 4000-s.This shearing force is proved can activated blood platelet.
Inlet pressure in 3 experiments is 8.13psi, and seepage remaining liquid pressure is 6.15psi.Pressure differs 2psi.Permeate pressure is essentially 0, and transmembrane pressure is 7.15psi.These pressure are highly stable in exchange, show not stop up film.The permeate flow velocity is about 26ml/ minute.
When Argatroban exists, the activation of its complete blocking platelet, thereby what on thromboelastogram, see is straight line.Fig. 9 shows the hematoblastic thromboelastogram that does not contain inhibitor.As this line separately shown in R value (being that grumeleuse begins to form the used time) average out to 10.7 minutes.After 15 times of volume-exchange, average R value is 10.75.In 4 experiments of the total of carrying out, 15 times of volume-exchange R value afterwards is equal to or less than baseline R value.According to thromboelastogram, reached and removed 99.99% inhibitor at least.
When hematoblastic slight dilution was taken into account in 15 times of volume-exchange processes, amplitude peak MA did not change with respect to baseline.This parameter has reflected the removal of Integrilin.
Figure 10 is illustrated in and adds the result that the Trap that before the inhibitor platelet carried out analyzes.TG-AUC is expressed as and is standard unit.The value of contrast is 67.Use Intersol carry out after 15 times of volume-exchange to platelet carry out the result of same analysis be 68 (Figure 11).This analysis is more responsive to depositing of Integrilin.Thereby this analysis shows that this inhibitor is removed basically fully.
It is hematoblastic functional also to use collagen to test as activator.Hematoblastic baseline value is 6 (Figure 12).The hematoblastic value of using Intersol to carry out obtaining after 15 times of volume-exchange removal inhibitor also is 6 (Figure 13).
Through the method for experiment described above, can easily accomplish in the platelet concentrate blood plasma and replace fully, no matter platelet concentrate is collected through Apheresis, tunica albuginea method or other any method.
More than describing is from instruction those skilled in the art purpose of embodiment of the present invention how, is not that intention details those skilled in the art through reading description with regard to obtainable conspicuous modification and variation.Yet all conspicuous like this modifications and variation all are intended to be included in by in the defined scope of the present invention of following embodiment.Only if the composition of asking for protection that can effectively realize purpose is contained in explanation especially in addition in the literary composition, said embodiment intention and by any step in sequence.
Claims (28)
1. from preparations of platelets, remove the method for anti-platelet agents and anticoagulant, said method comprises:
Preparations of platelets is flow through contain the filter tube of filter membrane, and pass through tangential flow filtration and from preparations of platelets, separate anti-platelet agents and anticoagulant.
2. method according to claim 1, wherein said filter membrane contain and are selected from following material: regenerated cellulose, cellulose acetate, polyamide, polysulfones, gather ethyl sulfone and their combination.
3. method according to claim 2, wherein said filter membrane contain polysulfones or gather ethyl sulfone.
4. method according to claim 1, the aperture of wherein said filter membrane are molecular cut off 3000 dalton to 0.5 micron.
5. method according to claim 1, the internal diameter of wherein said filter tube is 0.5mm at least.
6. the flow velocity that method according to claim 1, wherein said preparations of platelets flow through filter tube is 150-400ml/ minute.
7. method according to claim 1, wherein said extracting solution with the mode of adverse current in the filter tube outer loop.
8. method according to claim 7, wherein said extracting solution contains the sodium chloride of 0.9%w/v.
9. from preparations of platelets, remove the method for anti-platelet agents and anticoagulant, said method comprises:
Make preparations of platelets pass through the porous material that specificity combines anti-platelet agents and anticoagulant.
10. method according to claim 9, wherein said porous material comprises nanofiber.
11. method according to claim 10, wherein said nanofiber are cellulose nano-fibrous.
12. method according to claim 11, wherein said cellulose nano-fibrous diameter is 5-60nm.
13. method according to claim 10 is wherein modified said cellulose nano-fibrously, makes it that specific binding site of given anti-platelet agents or anticoagulant can be provided.
14. method according to claim 9, wherein said porous material comprise the enhancing composite membrane that contains 90% polyvinyl alcohol and 10% nanofiber.
15. method according to claim 9, wherein said nanofiber are biodegradable nanofiber.
16. method according to claim 15, wherein said biodegradable nanofiber comprise gather (glycolic) (PGA), gather (L-lactic acid) (PLLA), gather (lactic acid-altogether-glycolic) (PLGA) or their combination.
17. method according to claim 15 has wherein been carried out chemical modification through oxygen plasma treatment and hydrophilic acrylic acid (AA) situ-formed graft to the surface of said biodegradable nanofiber.
18. method according to claim 15, it is that 200-800nm, aperture are that 2-30 micron and porosity are the porous filter of 94-96% that wherein said biodegradable nanofiber forms thickness.
19. method according to claim 10, wherein said nanofiber are carbon nano-fiber.
20. method according to claim 19, wherein said carbon nano-fiber is the carbon nano-fiber through chemical modification.
21. utilize diafiltration from preparations of platelets, to remove the method for anti-platelet agents and anticoagulant, said method comprises:
Make preparations of platelets cycle through the hollow-fibre membrane that can from preparations of platelets, separate anti-platelet agents and anticoagulant,
Wherein in cyclic process, add diafiltration buffer, to keep the constant volume of preparations of platelets to preparations of platelets.
22. comprising, method according to claim 21, wherein said hollow-fibre membrane be selected from following material: regenerated cellulose, cellulose acetate, polyamide, polyurethane, polypropylene, polysulfones, polyether sulfone, Merlon, nylon, polyimides and their combination.
23. method according to claim 21, wherein said hollow-fibre membrane comprise polysulfones or gather ethyl sulfone.
24. method according to claim 21, the internal diameter of wherein said hollow filter membrane is 0.5mm at least, and the aperture is molecular cut off 3000 dalton to 0.5 micron.
25. from preparations of platelets, remove the method for anti-platelet agents and anticoagulant, said method comprises:
Make preparations of platelets flow through the filter membrane surface, and from preparations of platelets, separate anti-platelet agents and anticoagulant through tangential flow filtration.
26. method according to claim 25, the aperture of wherein said filter membrane are molecular cut off 3000 dalton to 0.5 micron.
27. be used for removing from preparations of platelets the filter of anti-platelet agents and anticoagulant, said filter comprises process and modifies and the nanofiber of ability specificity combination anti-platelet agents or anticoagulant.
28. filter according to claim 27, wherein said nanofiber is selected from: cellulose nano-fibrous, biodegradable nanofiber and carbon nano-fiber.
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US12/792,259 US9095818B2 (en) | 2009-06-15 | 2010-06-02 | Method of filtering platelets to remove antiplatelet and anticoagulant agents |
US12/792,259 | 2010-06-02 | ||
PCT/US2010/037203 WO2010147763A2 (en) | 2009-06-15 | 2010-06-03 | A method and device for filtering platelets |
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Also Published As
Publication number | Publication date |
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WO2010147763A3 (en) | 2011-04-21 |
US8470521B2 (en) | 2013-06-25 |
CA2760012A1 (en) | 2010-12-23 |
EP2442848A4 (en) | 2016-03-09 |
EP2442848A2 (en) | 2012-04-25 |
US9095818B2 (en) | 2015-08-04 |
US20120315619A1 (en) | 2012-12-13 |
WO2010147763A2 (en) | 2010-12-23 |
US20100316988A1 (en) | 2010-12-16 |
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